Project Summary Worldwide, over 40 million people have been diagnosed with a neurodegenerative disease, such as amyotrophic lateral sclerosis (ALS), Parkinson's Disease, or Alzheimer's Disease. Yet, with an annual cost-of- care greater than $226 billion, there have yet to be effective drugs and delivery strategies developed to treat these diseases. The overall goal of this project is to develop technologies that target uptake and delivery, via the autonomic nervous system, of biologics (e.g. proteins, peptides, or nucleic acid drugs) to the central nervous system (CNS). Since the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) protect the CNS from drug-delivery, potential therapies for these neurodegenerative diseases have not been realized, in part, due to the lack of delivery technologies. We base our approach on the knowledge that viruses are able to target neurons in the periphery to facilitate uptake and retrograde transport into the CNS. We will screen a recombinant phage display library for uptake and delivery to the brain and spinal cord after intraperitoneal (IP) injection. Next-generation DNA sequencing (NGS) analysis will be used to analyze tissues for high-frequency clones that transport into the CNS. We hypothesize that coupling an in vivo phage display screen with NGS will enable an empiric, high-throughput analysis of consensus sequences to engineer a targeting ligand for delivery to the CNS. In this work, we will optimize peptide ligands and evaluate these peptides in vivo for their ability to enhance protein-drug accumulation in the brain and spinal cord after IP injection.